4-(P-Fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine

ABSTRACT

A novel process for the preparation of 4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine and the acid addition salts thereof is disclosed.

This is a continuation, of application Ser. No. 736,966, filed Oct. 29,1976 and now abandoned.

The present invention relates to4-(p-fluorobenzyl)-1-[3-(p-fluorobenzyl)propyl]piperidine, its acidaddition salts, and a novel procedure for the preparation thereof.

4-(P-Fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine andacid-addition salts thereof are disclosed in U.S. Pat. No. 3,576,810.The compound is prepared by the condensation of4-(p-fluorobenzoyl)piperidine hydrochloride and 3-(p-fluorobenzoyl)propylchloride in a lower alkanol solvent in the presence of an alkalimetal carbonate.

In the foregoing synthesis the 3-(p-fluorobenzyl)propyl chloridereactant is preferably employed in the form of its ketal, i.e., as2-(p-fluorophenyl)-2-(3-chloropropyl)-1,3-dioxolane. The use of theketal reactant results in increased yields of final product having ahigh degree of purity. The2-(p-fluorophenyl)-2-[3-(p-fluorobenzoylpiperidino)propyl[-1,3-dioxolanethus obtained is treated with dilute mineral acid to regenerate the freecarbonyl group.

The method referred to hereinabove requires the added steps ofpreparation of the ketal and the regeneration of the free ketone. Wehave now found that4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidinehydrochloride can be prepared in good yield and in very pure form freeof interfering by-products by converting N-γ-carboxypropylisonipecoticacid into the di-acid chloride and reacting the di-acid chloride withtwo moles of fluorobenzene. The hydrochloride salt of the desiredproduct is obtained directly in substantially pure form and is readilypurified by recrystallization.

It is therefore an object of the present invention to provide a novelprocess for the preparation of4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidinehydrochloride. Another object is to provide a novel process for thepreparation of4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidinehydrochloride in good yield and in very pure form free of contaminatingby-products. Additional objects will become apparent from thedescription which follows and the appended claims.

The following illustrates the novel process of the present invention.##STR1##

According to the novel process of the present invention,N-γ-carboxypropylisonipecotic acid II is converted into the di-acidchloride hydrochloride III by using a suitable chlorinating agent as,for example, thionyl chloride, phosphorous trichloride or phosphorouspentachloride. The reaction is carried out in a suitable inert solventsuch as dichloromethane, trichloromethane, carbon tetrachloride,fluorobenzene, benzene, toluene or the like. Fluorobenzene represents apreferred solvent as the chlorination and the reaction of the di-acidchloride with fluorobenzene can be carried out as a single step withoutisolation of the di-acid chloride. The condensation of the di-acidchloride and fluorobenzene is carried out in the presence of a suitableLewis acid, aluminum chloride being preferred, to give4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl) propyl]piperidinehydrochloride I.

The foregoing general description is exemplified by the followingpreparation and examples which are not to be construed as limiting.

PREPARATION 1 Ethyl N-γ-carbethoxypropylisonipecotinate.

Ethyl isonipecotinate (125.77 g., 0.80 mole) is dissolved in 1,000 ml.of acetone, and 166.0 g. (1.2 mole) of potassium carbonate are added.Ethyl γ-bromobutyrate (171 g., 0.88 mole) is added dropwise withstirring at 20°-25° C. The mixture is heated for 24 hours at reflux(56°-60° C.). The mixture is cooled to 10°-15° C., the inorganic saltsare removed by filtration, and the acetone filtrate is concentrated. Theoily residue is distilled at 140°-142° C. (0.3 mm) to give 195-199 g.(90-92%) of a colorless oil.

Ethyl γ-chlorobutyrate can be used in the condensation giving theproduct in somewhat lower yield (54%).

EXAMPLE 1 N-γ-Carboxypropylisonipectic Acid Hydrochloride.

To a stirred mixture of 189.9 g. of ethylN-γ-carbethoxypropylisonipecotinate and 300 ml. of water is addedrapidly 200 ml. of concentrated hydrochloric acid. The temperature risesrapidly to 50° C. giving a clear solution. The mixture is refluxed for3-4 hours, the temperature is lowered to about 45° C. and vacuum appliedto remove as much water as possible. The pasty residue is treated with350 ml. of isopropanol, cooled to 0°-5° C. and the crystalline productcollected and washed with isopropanol. The dried colorless crystallineproduct (70°-80° C.) weighed 143-2 g. (81.47%) and melted at 202°-203°C.

N-γ-Carboxypropylisonipecotic acid hydrochloride is very soluble inwater, slightly soluble in methanol and 95% ethanol and insoluble inabsolute ethanol, isopropanol, chloroform and acetone.

EXAMPLE 2

4-(p-Fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidineHydrochloride.

N-γ-Carboxypropylisonipecotic acid hydrochloride (50.3 g., 0.2 mole) issuspended in 250 ml. freshly distilled fluorobenzene, 1 ml.dimethylformamide (catalyst) is added, followed by the dropwise additionof 50 g. (0.42 mole) thionylchloride with stirring. Upon completion ofthe addition, the reaction mixture is heated cautiously to 50°-55° C. atwhich temperature vigorous formation of hydrochloric acid and sulfurdioxide commences. The temperature is maintained at 50°-55° C. until aclear reduction of the gas formation is observed, and then the mixtureis heated slowly to reflux (78°-85° C.) at which temperature once againformation of gas commences. After heating at reflux for five hours,about 50 ml. of fluorobenzene are removed by distillation (in order toremove excess thionylchloride), and the dark colored mixture is cooledto 15° C. While the temperature is maintained below 30° C., 93.4 g. (0.7mole) of anhydrous aluminum chloride are added in portions. The reactionbetween fluorobenzene and the di-acid chloride occurs with developmentof heat and hydrogen chloride. Stirring at a temperature below 30° C. iscontinued for some time, and the mixture is then heated slowly to reflux(80°-85° C.) and maintained at reflux for six hours. The reactionmixture is cooled to 10°-15° C. and poured with stirring onto 400 g.crushed ice. During this operation a temperature below 30° C. ismaintained. From this mixture as much fluorobenzene as possible isremoved by distillation under slight vacuum (70-90 mm) and a pottemperature of 35° C. (foaming) to facilitate filtration of the product.The mixture is cooled to 5° C., the precipitate is removed by filtrationand mixed with 250 ml. acetone. The mixture is heated briefly (30minutes) to reflux, then cooled to 5° C. and the precipitate is removedby filtration, washed with acetone, and dried in vacuo at 60° C. Thedried tan colored product weighed 57 g. (70% yield).

The crude hydrochloride (48 g.) is dissolved in 960 ml. water heated toboiling, treated with activated charcoal and filtered while hot. Thefilter is rinsed with 75 ml. hot water. The filtrate is cooled to 0°-5°C. for five hours; the colorless crystals are removed by filtration,washed with cold water and dried in vacuo at 70° C. The dried whitecrystalline product weighed 35.8 g. (74.6%) and melted at 260° C.(dec.).

The free base 4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine can be readily obtained by partition of thehydrochloride salt between chloroform and dilute aqueous base,separation and drying of the chloroform solution and concentration ofthe dried solution under reduced pressure. The free base thusly obtainedcan then be converted into any desired acid addition salt by reactingstoichiometric amounts of the free base and an inorganic or organic acidin a suitable lower alkanol solvent as, for example, ethanol orisopropanol and precipitating the acid addition salt thus formed by theaddition of ether.

We claim:
 1. Ethyl N-γ-carbethoxypropylisonipectinate. 2.N-γ-carboxypropylisonipecotic acid hydrochloride.